A new combinatorial strategy to selectively manipulate reactive astrocytes in disease

选择性操纵疾病中反应性星形胶质细胞的新组合策略

• 批准号: 9890020
• 负责人: Todd A Fiacco
• 金额: $ 18.48万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890020
• 关键词: Address; Alzheimer' s Disease; Astrocytes; Back; Brain; Brain Diseases; Cells; Cerebral Edema; Chronic; Communities; Data; Development; Diphtheria Toxin; Disease; Disease Progression; Effectiveness; Electroencephalography; Epilepsy; Epileptogenesis; Expression Profiling; Foundations; Gene Expression; Generations; Genetic Recombination; Glial Fibrillary Acidic Protein; Goals; Histologic; Hour; Injury; Ischemia; Kainic Acid; Knock-in Mouse; Knowledge; LCN2 gene; LoxP-flanked allele; Measures; Medical; Mission; Molecular; Monitor; Mosaicism; Mus; Neurodegenerative Disorders; Neuroglia; Neurological Models; Neurons; Outcome; Parkinson Disease; Pathogenesis; Pathway interactions; Process; Public Health; Reporter; Research; Role; Saline; Signal Pathway; Signal Transduction; Stroke; Tamoxifen; Temporal Lobe Epilepsy; Testing; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Viral; Work; astrogliosis; brain tissue; cell type; combinatorial; effective therapy; experimental study; genetic manipulation; hippocampal sclerosis; improved; insight; male; mind control; mouse model; nervous system disorder; new technology; novel; novel strategies; promoter; virtual

PROJECT SUMMARY Common to virtually all neurodegenerative diseases and brain disorders are changes in a glial cell type called an astrocyte, which become “reactive”. Astrocytes ordinarily provide critical support for neurons and only turn into reactive astrocytes (RAs) following injury or development of disease. A longstanding issue which has remained unknown is whether RAs contribute to, or help alleviate, disease progres- sion. Our long-term goal is to increase understanding of the molecular and cellular underpinnings of diseases and disorders of the nervous system through increased understanding of the role of reactive astrocytes. The objective of this proposal is to deliver a new strategy to selectively alter (eliminate, in- crease, or decrease) the function of only RAs at any point in the progression of nervous system disor- ders. One such disorder for which new treatments are needed is epilepsy. Despite being the third most common neurological disorder in the U.S. after Alzheimer’s disease and stroke, epilepsy is among the least understood of the major chronic medical conditions. Two aims are proposed, with the goal of characterizing this new strategy and providing proof-of-principle for using the approach for the selective manipulation of RAs in disease: In Aim 1, we will first characterize a novel reactive astrocyte inducible Cre transgenic strategy to selectively manipulate RAs in brain disease. In Aim 2, we will then use the new approach to either selectively eliminate RAs or reprogram them back into non-reactive astrocytes at various stages during the development of epilepsy. Our work will provide new knowledge on the pro- tective vs. detrimental roles of reactive astrocytes in the development of epilepsy. The rationale for the proposed research is that new insight into the role of reactive cell types in disease is an important goal for the development of more efficacious treatments. We anticipate that this research will be transforma- tive, as we will introduce to the research community a powerful new strategy to investigate the role of reactive astrocytes in any disease or disorder of the nervous system.

项目摘要 几乎所有神经退行性疾病和脑部疾病的常见是神经胶质细胞类型的变化 被称为星形胶质细胞，该星形胶质细胞通常为神经元提供关键的支持 在疾病的损伤或发展后，变成反应性星形胶质细胞（RAS） 尚不清楚的问题是RAS贡献 我们的长期目标是增加对分子和细胞基础的理解 通过增加对反应性作用的了解，神经系统的疾病和疾病 星形胶质细胞。 折痕或减少）该项目在神经系统进展中的功能 - DERS。 阿尔茨海默氏病和中风后，美国常见的神经系统疾病，癫痫是 对主要的慢性医疗条件最少了解。 表征这种新策略，并提供原理证明选择方法 疾病中RAS的操纵：在AIM 1中，我们将首先描述一种新型的反应性星形胶质细胞 CRE转基因策略在AIM 2中选择性操纵RAS。 选择性地消除RA或将其重新编程为无反应的星形胶质细胞的新方法 在癫痫发育期间的各个阶段。 反应性星形胶质细胞在癫痫发育中的作用与有害作用。 支撑研究是，新手进入反应性细胞在疾病中的作用一个重要目标 为了发展更有效的治疗方法。 Tive，因为我们将向社区介绍一项有力的新战略，以调查 神经系统疾病中任何疾病中的反应性星形胶质细胞。